Monkeypox, orf, and molluscum contagiosum viruses cause the most frequent poxvirus infections worldwide. Of these, monkeypox virus has the greatest potential to cause significant disease in human populations either as a natural infection or through a criminal event. Unlike smallpox, person-to-person transmission of monkeypox virus is very inefficient, and there is rarely more than three generations of transmission from an index case. With cessation of the smallpox vaccination program in the Sub-Saharan region of Africa in 1982, and the increased encroachment of humans into habitat maintaining animal reservoirs of monkeypox virus, this virus is reemerging as a human pathogen. Increased frequency of human infections provides the opportunity for selection of genotypes that can be maintained in human populations without the necessity of periodic reintroductions from animal reservoirs. Thus monkeypox virus has the potential to become more than a nuisance zoonosis. The 2003 outbreak of human monkeypox in the Midwest indicated how little we know concerning the natural biology of this virus, and its potential to cause human disease. African rodents imported from Ghana into the U.S. showed none of the expected signs of a lethal infection with monkeypox virus (e.g. conjunctivitis, lymphadenopathy and skin lesions) yet were able to efficiently transmit the disease to prairie dogs that were responsible for 71 cases of human monkeypox. Although much research has been done on simian monkeypox, the monkey like the human is thought to be an incidental host. There is a lack of information on monkeypox virus biology in rodent species that in Africa may act as natural reservoirs. This proposal is aimed at studying the biology of monkeypox virus in susceptible rodent species that will permit the evaluation of monkeypox virus transmissibility, virulence, and host range. This information will contribute to our understanding of epizootic outbreaks of disease. Furthermore, since human monkeypox is indistinguishable from smallpox, a small animal monkeypox model that recapitulates natural disease may provide us with insights into human monkeypox and smallpox. And finally, a small animal model that yields a fulminant lethal infection at low doses of virus (<102 PFU) could provide an intermediate step between current mouse and monkey models for evaluation of the efficacy of vaccines and antivirals against smallpox.